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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

 
Antisense-mediated splicing correction as a therapeutic approach for p53 K120R mutation
Doyeong Kim1,# (Post-doctoral), Sang-Min Park1,# (Professor), Seo-Young Lee2 (Technical Researcher), Jinchul Kim3 (Senior Research), Han-Byul Jung2,5 (Technical Researcher), Young Sook Kim4 (Principal Researcher), Sun-Ku Chung2,5,* (Principal Researcher)
1College of Pharmacy, Chungnam National University,
2Division of KM Science Research, Korea Institute of Oriental Medicine,
3Ageing Research Center, Korea Research Institute of Bioscience and Biotechnology,
4Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine,
5Korean Convergence Medical Science, University of Science and Technology
Abstract
The TP53 c.359A>G mutation significantly disrupts the expression of the major TP53 transcript variant encoding p53 K120R by generating a new splice donor site. An antisense morpholino oligomer (AMO) targeting this mutation successfully restored normal splicing and the expression of the major TP53 variant. Given that p53 exerts its tumor suppressor function by regulating target genes responsible for growth arrest or apoptosis, the p53 K120R protein enhanced by AMO exhibits impaired transcriptional regulation of CDKN1A, a key growth arrest gene, while maintaining normal induction of the pro-apoptotic BBC3 gene. As a result, the mutant p53 K120R protein shows a defective cell growth arrest phenotype but retains apoptotic function, suggesting that it may still possess some tumor suppressor activity. Furthermore, lysine 120, known to provide a critical acetylation site for p53 activation, highlights the relevance of acetylation in tumor suppression through studies of the p53 K120R mutant. However, our findings demonstrate that targeting mutant TP53 mRNA with AMO is essential for restoring p53 function. In conclusion, this study emphasizes the potential of AMO-mediated splice correction as a therapeutic approach for TP53 mutations.
Abstract, Accepted Manuscript [Submitted on July 26, 2024, Accepted on September 11, 2024]
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